Levodopa on Decrease of Plasma Taurine Level in Parkinsons

Levodopa on Decrease of Plasma Taurine Level in ParkinsonsTitleLevodopa aggravates the decrease of plasm taurine take in Parkinson Disease report wordsParkinsons sickness (PD) Oxidative stress Levodopa Toxicity TaurineHighlightsThis is the first determine to explore chronic use of levodopa on the change of blood blood blood germ plasm taurine level.Plasma taurine levels were significantly lower in both interact and untreated PD than in healthy controls.Much lower plasma taurine level was undercoat in treated PD than the untreated.Plasma taurine level was negatively associated with cumulative dosage of levodopa in PD.AbbreviationsPD, Parkinsons disease MMSE, minimental state examination DA, dopamine ROS, reactive oxygen species MAO, monoamine oxidase CNS, central nervous placement H2O2, peroxide SOD, superoxide dismutase CSF, cerebrospinal fluid lineationIn recent years, it has gained much and more focus that oxidative stress is implicated in the pathophysiology of Parkins ons disease(PD) as easily as the potential perniciousness of levodopa to nigral cells. Also, an increasing body of evidence suggests that taurine plays an important role in anti-oxidant function. This study aimed to investigate the relationship between plasma taurine level and clinical variables and the cumulative dosage of levodopa in PD patients. 44 treated patients with PD ( all receive levodopa), 68 untreated patients with PD and 96 age-and sex-matched healthy controls were recruited. Clinical info such as age, gender, duration, Hoehn and Yahr stage and medication history were collected. Approximate cumulative dosage of levodopa was calculated to indicate the toxicity of chronic intake of levodopa. Plasma levels of taurine were measured by HPLC-RF. Plasma taurine levels were significantly lower in both treated and untreated PD than healthy controls. Much lower plasma taurine level was found in treated PD than the untreated. Furthermore, plasma taurine level was negatively asso ciated with cumulative levodopa dosage in PD. Our preliminary study indicates that taurine may play an important role in pathophysiology of PD and toxicity of chronic levodopa treatment.IntroductionPD is the second most common neurodegenerative disorder characterized by selectively loss of dopamine (DA)-containing neurons in the substantia nigra and a concomitant reduction of DA in the striatum. Levodopa, a natural precursor of DA, has been the favorable standard therapy for PD patients for decades 1. However, thepathophysiology of PD is up to now still poorly understood.More and more focus comes to that oxidative stress is implicated in the pathophysiology of PD, manifested as protein oxidation, lipid peroxidation, DNA oxidation and so on 2. Moreover, there has been an increasing concern that levodopa may be toxic to dopaminergic neurons 3-5, mainly because of its potential to autoxidize from a catechol to a quinine and to generate other forms of reactive oxygen species (ROS) 6.Tau rine, an endogenous amino acid (2-aminoethanesulfonic acid), is abundant in excitable tissues such as brain, retina, cardiac muscle and careworn muscle 7. Both in vitro and in vivo studies together demonstrate that the anti-oxidative activity of taurine is a vital avenue of cytoprotection 8-12. Additionally, our previous study has inform that plasma taurine level was lessen in patients with PD 13. Also, there are lines of evidence that taurine may exhibit cyto custodial effect by acting as a scavenger for harmful free radicals produced by DA or levodopa 14, 15.However, the precise anti-oxidative mechanism of taurine involved in both PD pathophysiology and putative(prenominal) toxicity of levodopa still remains uncertain. Furthermore, few studies have been done to address the relationship between plasma taurine level and clinical variables as sound as the toxic effects of chronic levodopa memorial tablet. Hence, in our study, we specifically explored the underlying impact on pla sma taurine level because of long-term levodopa intake in PD patients.2. Patients and methods2.1 patientsPatients with PD, diagnosed based on UK Parkinsons disease Brain Bank criteria by two movement disorders specialists (Kezhong Zhang and Lian Zhang), were included in this study 16. Clinical reading were collected by the same medical worker and the Hoehn and Yahr stage was used to evaluate the severity of disease 17. Since the anti-parkinsonian drugs may affect plasma taurine level, thorough medication histories were completely obtained through family and patient recall, personal medical chart, as well as computerized patient information organization in our hospital. Exclusion criteria were abnormal or secondary Parkinsonism, impaired cognitive status (assessed by the minimental state examination (MMSE) 18), previous neurosurgical treatment for PD, significant laboratory, medical, or psychiatric abnormalities, or any condition that might affect plasma taurine level. Age -and g ender-matched controls were also recruited, devoid of neurological disease, poor nutritional status, dementia or a family history of PD. The research project was approved by the ethics committee of the first affiliated hospital of Nanjing medical university and all the participants were given a full explanation and consented to the study in writing.2.2 Calculation of the cumulative levodopa standardIn order to assess the underlying toxicity of levodopa , an approximation of the cumulative levodopa amount was calculated based on the following equation (modified according to that ofNagatsuet al. 19) cumulative levodopa amount g =daily amount of levodopamg * duration of levodopa intake month *30 d/month*0.001g/mg.2.3 Measurement of taurine levels from plasmaPlasma taurine levels were measured as previously described 13.2.4 Statistical analysisAll statistical analyses were performed in SPSSV.20.0 (SPSS, Chicago, IL, USA). The normality of the distribution of all continuous variables wa s realized by ShapiroWilk statistic. Homogeneity of variance was assessed by Levenes test. Group comparisons were made using chi-square test for categorical variables, and one-way ANOVA as well as the Kruskal-Wallis test which was followed by the Mann-Whitney U test with Bonferroni correction for multiple comparisons (controls vs untreated patients, controls vstreated patients, untreated patients vs treated patients), as appropriate, for continuous variables. The correlation significance was evaluated by Spearman rank correlation coefficient.The statistical significance was set at P 3. Results3.1. Demographic information, clinical variables and treatment status of PD Patients and ControlsThe demographic and clinical data of all subjects are summarized in Table 1. Gender and age did not differ among three groups, while the duration was longer (2.901.50vs. 1.451.14y, pHoehn and Yahr stage was higher (1.970.71vs. 1.670.72, pdetailed information on the treatment status see Table 2).3. 2. Plasma taurine level in PD patients and controlsNotably, both treated PD (41.1622.72mol/L) and untreated PD (57.3831.05mol/L) were found to have significantly decreased plasma taurine levels compared to healthy controls (133.8345.91mol/L, P for both comparisons for the two PD groups were considered as a whole, the mean taurine level was also significantly lower than that in the control group (P3.3. Association between plasma taurine level and clinical variables and treatment status.Plasma taurine levels showed, however, no statistically significant association with age, duration, as well as Hoehn and Yahr stage in treated PD, untreated PD or all patients (Data not show). Interestingly, significant correlation was found between taurine level and cumulative levodopa dosage (shown in Fig.2, rs =-0.351, P paroleAccording to our knowledge, this is the first study to explore chronic use of levodopa on the change of plasma taurine level. The major pass ons of this study are summarized as follows 1) inured and untreated PD were found to have significantly decreased plasma taurine levels compared to healthy controls. 2) Plasma taurine level was lower in treated PD than the untreated, and inversely tally with cumulative dosage of levodopa.Taurine, the most abundant amino acid in mammals, is widely distributed in central nervous system (CNS) 20 and its biosynthesis mainly takes place in the liver 21. In the CNS, the concentration of taurine is dependent on food and a complex transport system at the blood brain barrier 20. Hence, plasma taurine may partially reflect the pathological change in CNS of PD patients.Firstly, decreased plasma taurine level of patients with PD discovered in this study is in line with our previous work 13. Similarly, there have been some studies describe CSF (cerebrospinal fluid) taurine level was significantly decreased in PD when compared to healthy controls 19, 22. Previous studies provide evidence that taurine has a remarkable anti-ox idative function. Furthermore, in a study of PC12 cells, taurine exhibited a protective role against oxidative stress induced by peroxide (H2O2) through the alleviation of endoplasmic reticulum stress 12. Also, Castro-Caldas et al. 10 reported that pretreatment of TUDCA (an analogue of taurine) abrogated the level of ROS in MPTP-mice, thus further highlighting the anti-oxidative role in vivo and suggesting that TUDCA may modulate the intracellular oxidative environment via interfering with the cellular redox threshold. Moreover, it has been observed that significant increases in glutathione content and superoxide dismutase (SOD) activity were founded in the livers of the taurine-supplemented 6-OHDAinduced PD rats, which indicated that taurine may increase the defenses against oxidative annoy 11. Collectively, we assume that the decrease of plasma taurine level may result from chronic assumption of oxidants. Therefore, taurine may play an important neuroprotective role in the pathop hysiology of PD via its potent anti-oxidative activity.By contrast, both normal 23 and increased 24-26 CSF taurine levels were found in several previous studies. Moreover, no significant decreased plasma taurine was observed in Molina et al.s study 22. However, studies conductedby Lakke et al. 25, 26, Tohgi et al. 23 and Araki et al. 24 all had some limitations. For example, the controls were not well matched regarding gender and age. Additionally, different sample sizes and measurements may also partially explain the discrepancy of the results. Compared with those previous studies, we recruited relatively more patients in this study. Also, statistical analysis was well performed and measurement used in our study is more stable and sensitive.Nevertheless, we depart to observe correlation between plasma taurine level and age, duration and Hoehn and Yahr in treated PD, untreated PD or all PD. This may result from that only patients with relatively short duration (within 5 years) and low Hoehn and Yahr (within stage 3) were enrolled in our study, and the plasma taurine was probably not sensitive enough to examine the underlying correlation in early to medium stage PD patients. Therefore, further research including more stages of patients would bring more invaluable information on this point.Secondly, treated PD patients exhibited lower plasma taurine level than the untreated. Although the duration was longer and the Hoehn and Yahr stage was higher in treated PD than untreated PD, uncomplete of the two clinical variables was correlated with plasma taurine level in each group. More importantly, plasma taurine level significantly negatively correlated with cumulative dosage of levodopa. These data suggest that chronic treatment of levodopa may affect plasma taurine concentration.Previous studies have shown that levodopa has the capacity to form ROS by autoxidation from catechols to quinines 4. Interestingly, Biasetti et al. 27 found that taurine attenuated iron-c atalyzed quinine formation from levodopa. Also, some studies suggest that taurine may bind these toxic quinones 27, 28. Furthermore, there have been studies 29 showing that chronic systemic administration of levodopa to rodents depleted taurine pools, suggesting that taurine might play an important role in scavenging oxidants derived from levodopa metabolism in vivo. Therefore, we suppose that chronic consumption of taurine due to oxidants induced by levodopa may partially explain lower plasma taurine level in levodopa-treated PD than the untreated.However, there were different results observed in some other studies. Molina et al. 22 reported that no significant difference of CSF taurine level was found between levodopa-treated PD (n=21) and non-levedopa-treated PD (including untreated PD, n=8). The relatively small sample size may limit its interpretation. Moreover, Diederich et al. 30 found no significant decrease of plasma taurine after acute administration of levodopa. However, the acute levodopa administration may not fully refect the toxicity of cumulative levodopa intake.Nevertheless, our study has some limitations. Firstly, the population in this study is relatively small and the results essential be interpreted cautiously. Secondly, as this is only a retrospective study, future longitudinal study combining with biomarkers of oxidative stress will provide more important information on the role of levodopa in affecting the plasma taurine level as a neurotixic agent and of taurine as a anti-oxidative agent.In conclusion, our results showed that decreased plasma taurine level was found in patients with PD in comparison to healthy controls. Moreover, plasma taurine level was found lowed in treated PD than the untreated, and inversely correlated with cumulative levodopa dosage. Combining with previous studies, these data suggest taurine may play an important protective role in pathophysiology of PD and chronic administration of levodopa may have potential neurotoxicity by depleting taurine. Also, our pilot study could, at least, provide new insights into healthful strategies.